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PubMed2003

The nonenzymatic subunit of pseutarin C, a prothrombin activator from eastern brown snake (Pseudonaja textilis) venom, shows structural similarity to mammalian coagulation factor V.

Pseutarin C is a group C prothrombin activator from the venom of the eastern brown snake Pseudonaja textilis. It is a multi-subunit protein complex consisting of catalytic and nonenzymatic subunits similar to coagulation factor Xa and factor Va, respectively. Here we describe the complete sequence of the nonenzymatic subunit. Based on the partial amino acid sequence of the nonenzymatic subunit, degenerate primers were designed. Using a "walking" strategy based on sequentially designed primers, we determined the complete cDNA sequence of the nonenzymatic subunit. The cDNA encodes a protein of 1461 amino acid residues, which includes a 30-residue signal peptide, a mature protein of 1430 amino acid residues, and a stop codon. cDNA blot analysis showed a single transcript of approximately 4.6 kb. The deduced amino acid sequence shows approximately 50% identity to mammalian factor V and by homology has a similar domain structure consisting of domains A1-A2-B-A3-C1-C2. Interestingly, the B domain of pseutarin C is shorter than that of mammalian factor V (FV). Although most of the proteolytic activation sites are conserved, 2 of 3 proteolytic sites cleaved by activated protein C are mutated, and thus activated protein C is not able to inactivate this procoagulant toxin. The predicted posttranslational modifications, including disulfide bonds, N-glycosylation, phosphorylation, and sulfation, in pseutarin C are significantly different compared with bovine factor V. Thus, our data demonstrate that the nonenzymatic subunit of group C prothrombin activators is structurally similar to mammalian FV.

Amino Acid Sequence↗
PubMed2000

Recombinant VIIa concentrate in the management of bleeding following prothrombin complex concentrate-related myocardial infarction in patients with haemophilia and inhibitors.

Prothrombin complex concentrates (PCCs) and, more recently, activated prothrombin complex concentrates (APCCs), are widely used for the treatment of active bleeding in haemophiliacs with inhibitors. Myocardial infarction (MI), associated with the use of these concentrates, is a well-recognized, but uncommon, complication. We review the 14 previous cases published in the literature and describe two additional patients. MI related to the use of activated and non-activated PCCs predominantly affects young patients who often have no preceding history of, or risk factors for, MI and tends to be associated with large cumulative doses of concentrate. The most frequent pathological finding is myocardial haemorrhage, with no evidence of coronary artery atheroma or thrombosis. The management of further bleeding in these patients is difficult. We have safely used recombinant factor VIIa to treat bleeding in the immediate and long-term period following PCC-related MI.

Abdomen↗
PubMed1990

[Activated prothrombin complex preparations for the treatment of anticoagulant hemophilia. Preparation--method of operation--supply possibility].

The mechanism of the bypass activity of prothrombin complex preparatives for treatment of haemophiliacs with circulating anticoagulants remains unclear up to now. The following parameters had been tested with preparatives produced in a different manner (absorption by DEAE-Sephadex A 50, Molselekt A 50, tricalcium phosphate or aluminium hydroxide): Coagulation factors II, VII, IX, X and XII, activated factors VIIa and Xa as well as the FEIB activity. The bypass activity is strongly correlated to the factor VIIa content of the preparatives, however. These results agree with the statements by HEDNER and KISIEL, which had used a factor VII a concentrate for treatment of haemophilia complicated by circulating anticoagulants with success. According to farther investigations factor VII is correlated with the lipid content of the starting plasma. This knowledge is important for optimizing the production procedure of prothrombin complex preparatives with bypassing activity.

Absorption↗
PubMed1991

[The evaluation of lyophilized plasma as a reference standard for the prothrombin complex].

Analysis of a number of parameters of a lyophilized donor plasma reference sample to be used for the assessment of the prothrombin complex factors has shown the stability of this sample over the course of 14 months (a follow-up period). The sample may be used as a reference one in estimation of plasma prothrombin complex factor activities, and of PPSB activity. The reference sample activity should be estimated from the fresh donor plasma native pool, whose procoagulant activity is conventionally estimated as 100% or 1 U/ml. Use of a lyophilized reference sample helps obtain objective results compatible within this country, particularly so if all biologic reagents included in the test systems are standardized.

Blood Coagulation Factors↗
PubMed1983

The defective prothrombin consumption in Bernard-Soulier syndrome. Hypotheses from 1948 to 1982.

Bernard-Soulier syndrome (BSS) was described in 1948 as a constitutional platelet disorder characterized by giant sized platelets, a prolonged bleeding time, and a defect in prothrombin consumption. The accurate mechanisms of these abnormalities remain unexplained, especially the defect in prothrombin consumption on which we focus in this paper. Several hypotheses are proposed: firstly, a defective reaction between the platelet membrane, where the phospholipid composition is abnormal, and the proteins which initiate thromboplastin generation such as collagen, factor XI; secondly, an abnormal reaction between thrombin, whose synthesis is increased, and its receptor, possibly glycoprotein V, which is defective; lastly, as factor VIII/vW binding is diminished, an abnormal dissociation of the complex VIII/vW-VIIIc at the site of the platelet membrane, which leads to an inactivation of factor VIIIc.

Binding Sites↗
PubMed1984

Studies on prothrombin complex concentrates contact factors, complement components and proteinase inhibitors.

The behaviour of contact factors, complement components and antiproteases during the preparation of prothrombin complex concentrates by adsorption of the clotting components on DEAE-Sephadex has been studied. The pro-enzymes: factors XII, XI and prekallikrein were removed by pre-elution in function of the salt concentration. In contrast, high molecular weight kininogen was considerably enriched in PCC preparations. C4 of the complement system displayed an analogous behaviour. C1s reached a 4-5 fold plasma concentration but C3 only 30% of the normal plasma level. The prothrombin complex concentrate contained no antithrombin III nor alpha 2M nor alpha 2 antiplasmin but a three fold plasma concentration of C1-inactivator and a 15 fold increase of inter-alpha-trypsin inhibitor. NAPTT (Non Activated Partial Thromboplastin Time) ratios did not seem to be in accordance with either the presence or the absence of contact enzymes. Moreover 0.20 M NaCl appeared as the minimal pre-elution molarity necessary to ensure a NAPTT ratio above thrombogenic values. Molecular alteration of high molecular weight kininogen and C4 was observed and its significance discussed. Complex formation between C1-inactivator and proteases was shown to be another sign of undesirable proteolytic events.

Blood Coagulation Factors↗
PubMed1996

High purity factor IX and prothrombin complex concentrate (PCC): pharmacokinetics and evidence that factor IXa is the thrombogenic trigger in PCC.

Recent studies using assays for surrogate markers of thrombogenicity in man have demonstrated that activation of the coagulation system occurs following infusion of clinical doses of prothrombin complex concentrates (PCC) but not after the same doses of high-purity factor IX concentrates (HP-FIX) in patients with haemophilia B. Here we have investigated the mechanism of such thrombogenesis by applying assays that detect early-through to late-events in coagulation system activation in a pharmacokinetic cross-over study of 50 IU/kg PCC and a new HP-FIX product in haemophilia B patients. Satisfactory recoveries and half-lives were observed for both concentrates. HP-FIX caused no increases in thrombin-antithrombin III complex (TAT), prothrombin activation peptide fragment F1+2 (F1+2), factor X activation peptide (FXAP) or factor VIIa (FVIIa). In contrast the same dose of factor IX in the form of PCC was followed by significant increases over pre-infusion levels of TAT, F1+2 and FXAP, but not FVIIa. Elevations of FIXAP occurred after both HP-FIX and PCC but did not reach normal levels and were attributed to normalisation of the FIX concentration in those patients whose levels of FIXAP were initially low. We conclude that the thrombogenic trigger associated with PCC infusion occurs at the level of factor X activation. In the absence of any increase in FVIIa, we would attribute this to the likely presence of FIXa in the PCC.

Adult↗
PubMed2004

Sensitivity of commercial prothrombin time reagents to detect coagulation factor deficiencies in equine plasma.

The sensitivity of commercial prothrombin time (PT) tests was assessed based on a dilution series of equine pooled plasma (EPP) (experiment 1) and on 40 equine plasma samples with reduced activity of coagulation factors II, V, VII and X (experiment 2). Two different PT reagents (reagent 1, human placental thromboplastin; reagent 2, recombinant human tissue factor) were used according to the manufacturers' instructions (standard test, PT([ST])) and compared to a modified test procedure (modified test, PT([MT])) using sample dilution and fibrinogen addition. In all samples, sensitivity was lower (P<0.01) when using PT([ST]) with reagent 2 (0.20) than when using either PT([ST]) with reagent 1 (0.65) or PT([MT]) with both reagents (reagent 1, 0.60-0.75, reagent 2, 0.58-0.70, depending on sample dilution). The highest sensitivity was found for PT([MT]) when using a 1:20 sample dilution. In those samples in which at least one coagulation factor activity was decreased (by 20%; n=18), the sensitivity of PT([ST]) with reagent 2 (0.33) was found to be inadequate, in contrast to all other test procedures (0.83-0.94). This low sensitivity corresponded to shorter time intervals between different coagulation activity levels prepared by EPP dilution. The results indicate that adequate sensitivity of PT measurements in equine plasma can be achieved using a standard test procedure as long as a suitable reagent is used.

Animals↗
PubMed1996

Reliability of the international normalized ratio for monitoring the induction phase of warfarin: comparison with the prothrombin time ratio.

The International Normalized Ratio (INR) was introduced to reduce the variability of prothrombin time (PT) reporting. One potential problem with the use of the INR is the assumption that its reliability is reduced when it is used to monitor patients during the induction phase of treatment. This shortcoming arises because the model used to establish the INR system is based on the use of pooled plasma from patients stabilized on warfarin for at least 6 weeks. Because the prolongation of the PT by warfarin during the induction phase mainly reflects reduction in factor VII levels (whereas the prolongation of the PT after 6 weeks of stabilization reflects reductions in factors X, II, and VII), there exists a potential for loss of accuracy of the INR during warfarin induction. To overcome this potential problem, it has been suggested that the PT ratio should be used to report results during the induction phase of treatment and that the INR system should be reserved for reporting results after the patient has been stabilized. This approach is confusing to the clinician. In addition, the validity of this approach has never been demonstrated in a clinical study. To address this issue, we studied 43 patients for the first 5 days after they started warfarin therapy. We measured the PT in the same plasma samples from each patient with five different commercial thromboplastins. The variance in the PT ratios among the five thromboplastins was compared with the variance obtained with the INR values derived from the PT ratios when using the international sensitivity indexes provided by the manufacturer. Our results indicate that, even during the induction phase, there is less variance with the INR system than with the PT ratio system.

Anticoagulants↗
PubMed1976

Prothrombin complex concentrate (Konyne) in the treatment of hemophilic patients with factor VIII inhibitors.

Two prothrombin complex concentrates, Auto-Factor IX and Proplex, have been reported to be effective in controlling bleeding in hemophilic patients with factor VIII inhibitors. A third PCC, Konyne, was used to treat 64 bleeding episodes (130 infusions) in five hemophilic patients with factor VIII inhibitors. Prompt control of bleeding was observed in each instance with doses of 15 to 100 units of factor IX/kg; no complications were encountered. Konyne resulted in in vivo and in vitro shortening of the partial thromboplastin time of patients with factor VIII inhibitors, but the mechanism of action is unknown. If further studies confirm the efficacy and safety of PCC in the treatment of such patients, its use for this purpose could lead to significant saving of factor VIII concentrates.

Adolescent↗
PubMed1997

Pregnancies in a patient with congenital absence of prothrombin activity: case report.

Congenital hypoprothrombinemias are very rare, inherited disorders in which factor II (prothrombin) levels and/or activity are extremely low or absent. We report eight pregnancies in a patient with this disorder. Obstetric complications attributed to the coagulation disturbance included first-trimester bleeding in each pregnancy, miscarriage in four of the pregnancies, spontaneous maternal subarachnoid hemorrhage in one, and postpartum hemorrhage in one of four term pregnancies despite administration of clotting factor concentrate. The management of pregnancy in congenital hypoprothrombinemia, and issues of coagulation factor replacement, are discussed.

Abortion, Spontaneous↗
PubMed1998

Prothrombin deficiency results in embryonic and neonatal lethality in mice.

The conversion of prothrombin (FII) to the serine protease, thrombin (FIIa), is a key step in the coagulation cascade because FIIa triggers platelet activation, converts fibrinogen to fibrin, and activates regulatory pathways that both promote and ultimately suppress coagulation. However, several observations suggest that FII may serve a broader physiological role than simply stemming blood loss, including the identification of multiple G protein-coupled, thrombin-activated receptors, and the well-documented mitogenic activity of FIIa in in vitro test systems. To explore in greater detail the physiological roles of FII in vivo, FII-deficient (FII-/-) mice were generated. Inactivation of the FII gene leads to partial embryonic lethality with more than one-half of the FII-/- embryos dying between embryonic days 9.5 and 11.5. Bleeding into the yolk sac cavity and varying degrees of tissue necrosis were observed in many FII-/- embryos within this gestational time frame. However, at least one-quarter of the FII-/- mice survived to term, but ultimately they, too, developed fatal hemorrhagic events and died within a few days of birth. This study directly demonstrates that FII is important in maintaining vascular integrity during development as well as postnatal life.

Alleles↗
PubMed2005

Vitamin K status of preterm infants with a prolonged prothrombin time.

AIM: To investigate the vitamin K status of preterm infants who have a prolonged prothrombin time (PT) in the first month of life. METHODS: Measures of vitamin K status were assessed in 21 preterm infants who were found to have an abnormal PT, despite 0.2-0.5 mg vitamin K(1) prophylaxis at birth. RESULTS: All infants had normal or supraphysiological vitamin K(1) concentrations and undetectable or, in one infant, insignificant PIVKA-II, indicating adequate vitamin K status. CONCLUSION: In preterm infants born at <32 wk gestation who received > or = 0.2 mg vitamin K(1) after delivery, a prolonged PT in the first month of life is unlikely to be due to vitamin K deficiency.

Biomarkers↗
PubMed1987

Control of oral anticoagulant treatment by chromogenic prothrombin assay.

Doses of oral anticoagulants in 50 patients on long term treatment were easily and satisfactorily monitored over six months by an automated chromogenic assay of prothrombin (CPA). It is suggested that chromogenic assay of one or more of the vitamin K dependent coagulation factors would provide a readily standardised alternative to those conventional tests which depend on human brain derived reagents, now regarded as a biohazard.

Administration, Oral↗
PubMed1985

An analysis of the one-stage prothrombin time.

An analysis of the one-stage prothrombin time using thromboplastins highly (Thrombotest) and slightly (Normotest) sensitive to the Pivka (protein induced by vitamin K absence) inhibitor is presented. A one-tenth dilution of blood with 0.1 mol/l Na3 citrate was satisfactory even at an extreme packed cell volume (PCV). Whole blood and plasma were equally satisfactory as test materials; however, their accuracy and precision were greatly improved when a small sample size at a high coagulation activity and a large sample size at a low coagulation activity were used. The PCV correction method which corrected for the different Pivka inhibitor sensitivities of thromboplastins was preferable.

Biomarkers↗
PubMedDate not supplied

Prothrombin time standardization by correction of the Pivka inhibitor.

The standardization of prothrombin time (PT) assays needs two steps: (1) calibration of PT assays towards a reference assay or reference thromboplastin, (2) correction of PT assays according to the calibration. The present recommended calibration by clotting times is favored for the linearity between assays; the clotting times of abnormal plasma are partly prolonged due to the protein induced by vitamin K absence (Pivka) inhibitor. Calibration by coagulation activities also demonstrated linearity between PT assays; the regression line for abnormal plasma deviated from the line of identity due to differences in sensitivity of assays for the Pivka inhibitor. The corrected PT assays demonstrated similar results using calibration by clotting time or coagulation activities, but the correction was simpler for coagulation activities. Patient plasma was the preferable material in calibration by clotting times as well as by coagulation activities. The corrections between the reference assay and other PT assays were equal to the differences in sensitivities for the Pivka inhibitor. The corrected PT assays did not differ from the reference assay by statistical analysis; any of the six PT assays tested might be used as reference assay.

Biomarkers↗
PubMed1978

[A micro-method developed for prothrombin time assay (author's transl)].

Prothrombin time was measured by a newly developed micro-method using a plastic film available in the market (PARAFILM, American Can. Co.). The comparative study of this micro-method with that of Quick in rats disclosed a good correlation, with correlation coefficient of 0.951, supporting the usefulness of the method for examination of blood coagulability. The new method gave the physiological values of 9.8 sec in rabbits, 12.5 sec in dogs, 13.3 sec in mice, 14.8 sec in cats and 16.0 sec in rats, respectively. Among them, guinea pigs took the longest time of 25.3 sec for the coagulation.

Animals↗